Aminopyrimidine and aminopyridine anti-inflammation agents

ABSTRACT

Aminopyrimidine and aminopyridine (I) compounds, compositions and methods useful in the treatment of inflammatory, metabolic or malignant conditions, are provided herein.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present invention claims the priority benefit under Title 35U.S.C. 119(e) of U.S. Provisional Application Serial No. 60/338,312,filed Nov. 7, 2001, the disclosure of which is herein incorporated byreference This application incorporates by reference the disclosure ofpending U.S. patent application Ser. No. 10/004,287, filed Oct. 23,2001, titled “Anti-inflammation Agents,” inventors Michelle F. Browner,et al.

BACKGROUND OF THE INVENTION

[0002] Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1) arecytokines that have been implicated in a wide range of biologicalprocesses, including inflammation. The recruitment of immune cells tosites of injury involves the concerted interactions of a large number ofsoluble mediators. Several cytokines appear to play key roles in theseprocesses, particularly IL-1 and TNF. Both cytokines are derived frommononuclear cells and macrophages, along with other cell types.Physiologically, they produce many of the same proinflammatoryresponses, including fever, sleep and anorexia, mobilization andactivation of polymorphonuclear leukocytes, induction of cyclooxygenaseand lipoxygenase enzymes, increase in adhesion molecule expression,activation of B-cells, T-cells and natural killer cells, and stimulationof production of other cytokines. Other actions include a contributionto the tissue degeneration seen in chronic inflammatory conditions, suchas stimulation of fibroblast proliferation, induction of collagenase,etc. They have also been implicated in the process of bone resorptionand adipose tissue regulation. Thus, these cytokines play key roles in alarge number of pathological conditions, including rheumatoid arthritis,inflammatory bowel disease, diabetes, obesity, bone mass loss, cancer,neurological conditions such as ischemic stroke or closed head injuries,etc.

[0003] Cytokines trigger a variety of changes in gene expression intheir target cells by binding and activating their respective cognatereceptors, which sets in motion certain biochemical events, includingthe activation of otherwise latent transcription factors. Members of theNF-kB Rel family of transcription factors represent some of the mostprominent of these transcription factors, having been implicated in theregulation of genes involved in inflammation, cell proliferation,apoptosis, and several other basic cellular functions (I. M. Verma etal, Genes Dev. 9, 2723 (1995); Baichwal & Baeuerle, Curr. Biol. 7, 94(1997)).

[0004] The best studied member of this family of transcription factorsis NF-KB, which generally exists in cells as a heterodimer of twoproteins: p50 (NF-KB1) and p65 (RelA), although homodimers of theseindividual components are also possible (Baeuerle and Baltimore, Cell,53, 211 (1988); Baeuerle and Henkel, Annu. Rev. Immunol., 12, 141(1994)). NF-kB, in its inactive form, resides in the cytoplasm of cells,but migrates to the nucleus in response to various types of stimuli,such as pro-inflammatory cytokines (e.g., TNF and IL-1), ultravioletirradiation and viral infection (Verma, 1995; Baichwal, 1997; Cao et al,Science, 271, 1128 (1996)). TNF and IL-1 have been shown to be two keypro-inflammation agents in a wide variety of pathological conditions,including rheumatoid arthritis, septic shock, inflammatory boweldisease, dermal sensitization disorders, neurological trauma such asstroke or closed-head injuries, etc.

[0005] In its inactive state, the NF-kB heterodimer is held in thecytoplasm by association with inhibitory IkB proteins. Recently, thethree-dimensional structure of a NF-kB/IkB ternary complex has beensolved (Huxford et al, Cell, 95, 759 (1998); Jacobs et al, Cell, 95, 749(1998)). When cells are treated with the appropriate stimuli, such asIL-1 or TNF, intracellular signal transduction pathways are activatedthat lead to the eventual phosphorylation of IkB proteins on twospecific residues (serines 32 and 36 in IkB-alpha, serines 19 and 23 inIkB-beta). Mutation of one or both of these serine residues renders IkBresistant to cytokine-induced phosphorylation. This signal-inducedphosphorylation targets IkB for ubiquitination and proteosome-mediateddegradation, allowing nuclear translocation of NF-kB (Thanos andManiatis, Cell, 80, 529 (1995)). The only regulated step in the IkBdegradation pathway is the phosphorylation of IkB by IkB kinases (IKK)(Yaron et al, EMBO J. 16, 6486 (1997)).

[0006] Several intermediate steps in the TNF- and IL-1-activatedsignaling pathways that result in IkB phosphorylation have beenelucidated in recent years. The protein kinases MEKK1 and MLK3 have beenimplicated in the induction of IKK activity (Malinin et al, Nature, 385,540 (1997); Song et al, Proc. Natl. Acad. Sci. USA, 94, 9792 (1997); Leeet al, Proc. Natl. Acad. Sci. USA. 95, 9319 (1998); Hehner et al, Mol.Cell. Biol. 20, 2556 (2000); Wang et al, Nature, 412, 346 (2001)). Whilethe specific details remain somewhat unclear regarding how these orother intermediate proteins may interact with and/or stimulate IKKactivity in cells, significant progress has been made in elucidating theenzymes responsible for IkB phosphorylation. Two IKK enzymes, generallyreferred to as either IKK-alpha and IKK-beta (Woronicz et al, Science,278, 866 (1997); Zandi et al, Cell, 91, 243 (1997)) or IKK-1 and IKK-2(Mercurio et al, Science, 278, 860 (1997)) have been discovered. Bothforms of IKK can exist as homodimers and as IKK-alpha/IKK-betaheterodimers. Another recently discovered component of the IkB kinasecomplex is a regulatory protein, known as IKK-gamma or NF-κB-EssentialModulator (NEMO) (Rothwarf et al, Nature, 395, 297 (1998)). NEMO doesnot contain a catalytic domain, and thus it appears to have no directkinase activity and it probably serves a regulatory function. Existingdata suggest that the predominant form of IKK in cells is anIKK-alpha/IKK-beta heterodimer associated with either a dimer or atrimer of NEMO (Rothwarf et al, Nature 395, 297 (1998)).

[0007] Biochemical and molecular biology experiments have clearlyidentified IKK-alpha and IKK-beta as the most likely mediators of TNF-and IL-1-induced IkB phosphorylation and degradation, which results inNF-kB activation and upregulation of families of genes involved ininflammatory processes (Woronicz et al, Science (1997); Karin, Oncogene18, 6867 (1999); Karin, J. Biol. Chem. 274, 27339 (1999)). IKK-alpha andIKK-beta have very similar primary structures, displaying more than 50%overall sequence identity. In the kinase domain, their sequences are 65%identical.

[0008] Based on our present understanding of the critical role played byTNF and IL-1 in the wide array of pathological conditions describedabove, and the involvement of IKK-alpha and IKK-beta in the signaltransduction of both cytokines, the discovery of compounds that potentlyand selectively inhibit either of these kinases would result in a majoradvancement in the therapy of those conditions. In this application wedescribe a novel type of compounds which display such desirable activityprofile.

SUMMARY OF THE INVENTION

[0009] In one aspect, the present invention provides compounds useful inthe treatment of inflammatory, metabolic or malignant conditions, havingthe formula:

[0010] In Formula (I):

[0011] One of either V or X is N and the other is —CR_(a), or both V andX are —CR_(a) (where each R_(a) is independently hydrogen, alkyl,cycloalkyl or cycloalkylalkyl;

[0012] Y represents O, S or N(R), wherein R is H, CN, NO₂,(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl,(C₃-C₁₀)alkenyl or (C₂-C₁₀)alkynyl;

[0013] Z represents H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl orN(R²)(R³);

[0014] R¹ represents H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl,heterocyclyl, heterocyclylalkyl, aryl, aryl(C₁-C₄)alkyl,aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl,heteroaryl(C₁-C₄)heteroalkyl, —C(O)R¹¹ or alkylene-C(O)R¹¹;

[0015] R¹¹ is hydrogen, (C₁-C₆)alkyl or NR¹²R¹³ (where R¹² and R¹³ areindependently hydrogen, (C₁-C₆)alkyl or heteroalkyl);

[0016] R² and R³ are each independently H, (C₁-C₁₀)alkyl,(C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, or (C₁-C₁₀)heteroalkyl, or R² and R³ can becombined to form a 5-7-membered heterocyclyl ring;

[0017] R⁴ represents H, alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl;

[0018] A represents H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₁-C₆) haloalkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl,(C₁-C₁₀)heteroalkyl,heterocyclyl, heterocyclylalkyl, heterosubstitutedcycloalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl,heteroaryl(C₁-C₄)alkyl heteroaryl(C₁-C₄)heteroalkyl or R^(a)R^(b)NC(═X)—wherein R^(a) and R^(b) are independently hydrogen, (C₁-C₄) alkyl oraryl and X is O or S;

[0019] B represents a substituted or unsubstituted five- or six-memberedaromatic ring containing at least one nitrogen atom, and from 0 to 3additional heteroatoms, wherein the B ring substituents are selectedfrom halogen, CF₃, CF₃O, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino, andcarboxamido; and

[0020] U represents NR⁵, O or S, wherein R⁵ is H or (C₁-C₆)alkyl.

[0021] In another aspect, the present invention provides pharmaceuticalcompositions comprising one or more compounds of formula I in admixturewith a pharmaceutically acceptable excipient.

[0022] In another aspect, this invention provides processes for thepreparing compounds of Formula (I).

[0023] In yet another aspect, the present invention provides methods forthe treatment of an inflammatory, metabolic or malignant condition,comprising administering to a subject in need of such treatment acompound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Abbreviations and Definitions

[0025] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0026] “Acyl” means the group —C(O)R′, where R′ is hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl and aryl-alkyl.

[0027] “Alkyl” means a linear saturated monovalent hydrocarbon radicalor a branched saturated monovalent hydrocarbon radical having the numberof carbon atoms indicated in the prefix. For example, (C₁-C₆)alkyl ismeant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl,and the like. For each of the definitions herein (e.g., alkyl, alkenyl,alkynyl, alkylene, alkoxy, aralkyloxy etc.), when a prefix is notincluded to indicate the number of carbon atoms in an alkyl portion, theradical or portion thereof will have six or fewer main chain carbonatoms. In all terms where a prefix indicating the number of carbon atomsis used, the prefix applies to the alkyl portion immediately followingthe prefix. For example the term heteroaryl(C₁-C₄)heteroalkyl indicatesfrom one to four carbon atoms in the heteroalkyl portion.

[0028] “Perfluoroalkyl” refers to an alkyl group having the indicatednumber of carbon atoms, in which some of the attached hydrogen atomshave been replaced with fluorine atoms, in a number ranging from 1 tothe maximal number of hydrogen atoms on the alkyl group.

[0029] “Alkylene” means a linear saturated divalent hydrocarbon radicalor a branched saturated divalent hydrocarbon radical having the numberof carbon atoms indicated in the prefix and if unspecified up to sixcarbon atoms. For example, (C₁-C₆)alkylene is meant to includemethylene, ethylene, propylene, 2-methylpropylene, pentylene, and thelike.

[0030] “Alkenyl” means a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical having the number of carbonatoms indicated in the prefix and containing at least one double bond.For example, (C₂-C₆)alkenyl is meant to include ethenyl, propenyl, andthe like.

[0031] “Alkynyl” means a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical containing at least one triplebond and having the number of carbon atoms indicated in the prefix. Forexample, (C₂-C₆)alkynyl is meant to include ethynyl, propynyl, and thelike.

[0032] “Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means aradical —OR where R is an alkyl, aryl, arylalkyl, or heteroarylalkylrespectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy,pyridin-2-ylmethyloxy, and the like.

[0033] “Alkoxycarbonylalkyl” means a radical —R^(a)C(O)R^(b) where R^(a)is an alkylene group as defined above and R^(b) is an alkoxy group asdefined above e.g., methoxycarbonylethyl, ethoxycarbonylbutyl, and thelike.

[0034] “Aryl” means a monovalent monocyclic or bicyclic aromatichydrocarbon radical of 6 to 10 ring atoms which is optionallysubstituted independently with one to four substituents, preferably one,two, or three substituents selected from alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl, halo, nitro, cyano, cyanoalkyl, hydroxy,alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl,haloalkoxy, heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl or phenylalkyl), —S(O)_(n)—R^(d) (where n is aninteger from 0 to 2, and where when n is 0, R^(d) is hydrogen, alkyl,cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) is alkyl,cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, ordialkylamino), —NS(O)₂R^(f) (where R^(f) is alkyl or aryl), —NHCOR^(c)(where R^(c) is amino, alkylamino, dialkylamino or (C₁-C₄)alkoxy),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl), —(CR′R″)_(n)S(O)_(n)—R^(d)(where n is an integer from 0 to 2, and where when n is 0, R^(d) ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2,R^(d) is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino,monoalkylamino, or dialkylamino), —(CR′R″)_(n)—CONR^(a)R^(b) (where n isan integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl,and R^(a) and R^(b) are, independently of each other, hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl (C₁-C₄) alkoxy or phenylalkyl), orany 2 adjacent carbon atoms are substituted by —O(CH₂)_(n)O— (where n is1 or 2). More specifically the term aryl includes, but is not limitedto, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, cyanophenyl, and thederivatives thereof.

[0035] “Arylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group (having six or fewer main chain carbon atoms) and R^(b)is an aryl group as defined herein, e.g., benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like with the notationaryl(C₁-C₄)alkyl indicating from one to four carbon atoms in thealkylene chain.

[0036] “Arylheteroalkyl” means a radical —R^(a)R^(b) where R^(a) is anheteroalkylene group and R^(b) is an aryl group as defined herein, e.g.,2-hydroxy-2-phenyl-ethyl, 2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl, andthe like.

[0037] “Cycloalkyl” means a saturated monovalent cyclic hydrocarbonradical having the number of ring carbon atoms indicated in the prefixand if unspecified from three to seven ring carbon atoms. For example,(C₃-C₇) cycloalkyl includes cyclopropyl through cycloheptyl. Thecycloalkyl may be optionally substituted independently with one, two, orthree substituents selected from alkyl, optionally substituted phenyl,or —C(O)R (where R is hydrogen, alkyl, haloalkyl, amino, acylamino,mono-alkylamino, di-alkylamino, hydroxy, alkoxy, or optionallysubstituted phenyl). More specifically, the term cycloalkyl includes,for example, cyclopropyl, cyclohexyl, phenylcyclohexyl,4-carboxycyclohexyl, 2-carboxamidocyclohexyl,2-dimethylaminocarbonyl-cyclohexyl, and the like.

[0038] “Cycloalkyl-alkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a cycloalkyl group as defined herein, e.g.,cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, andthe like. The prefix indicating the number of carbon atoms (e.g., C₃-C₇)refers to the number of ring carbon atoms in the cycloalkyl portion.

[0039] “Haloalkyl” means alkyl substituted with one or more same ordifferent halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and thelike, and further includes those alkyl groups such as perfluoroalkyl inwhich all hydrogen atoms are replaced by fluorine atoms. The prefix“halo” and the term “halogen” when used to describe a substituent, referto —F, —Cl, —Br and —I.

[0040] “Heteroalkyl” means an alkyl radical as defined herein with one,two or three substituents independently selected from cyano, —OR^(a),—NR^(b)R^(c), and S(O)_(n)R^(d) (where n is an integer from 0 to 2 );with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom of the heteroalkyl radical. R^(a) ishydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- ordi-alkylcarbamoyl. R^(b) is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, aryl or aralkyl. R^(c) is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl,carboxamido, mono- or di-alkylcarbamoyl, alkylsulfonyl, —C(O)R′, or—S(O)_(n)R′ (where n is an integer from 0 to 2; where R′ is hydrogen,alkyl or aryl). R^(d) is hydrogen (provided that n is 0), alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, amino, mono-alkylamino,di-alkylamino, or hydroxyalkyl. Representative examples include,2-hydroxyethyl, 2,3-dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl,2-cyanoethyl, and 2-methylsulfonyl-ethyl. Additionally, the prefixindicating the number of carbon atoms (e.g., C₁-C₁₀) refers to the totalnumber of carbon atoms in the portion of the heteroalkyl group exclusiveof the cyano, —OR^(a), —NR^(b)R^(c), or —S(O)_(n)R^(d) portions.

[0041] “Heteroaryl” means a monovalent monocyclic or bicyclic radical of5 to 12 ring atoms having at least one aromatic ring containing one,two, or three ring heteroatoms selected from N, O, or S, the remainingring atoms being C, with the understanding that the attachment point ofthe heteroaryl radical will be on an aromatic ring. The heteroaryl ringis optionally substituted independently with one to four substituents,preferably one or two substituents, selected from alkyl, cycloalkyl,cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR(where R is hydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″)_(n)—COOR(where n is an integer from 0 to 5, R′ and R″ are independently hydrogenor alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenylor phenylalkyl), or —(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integerfrom 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R^(a)and R^(b) are, independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl or phenylalkyl). More specifically the termheteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl,thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl,pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl,tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl,quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl,benzisoxazolyl or benzothienyl, and the derivatives thereof.

[0042] “Heteroarylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heteroaryl group as defined herein, e.g.,pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0043] “Heterocyclyl” means a saturated or unsaturated non-aromaticcyclic radical of 3 to 8 ring atoms in which one or two ring atoms areheteroatoms selected from O, NR (where R is independently hydrogen,alkyl, or any of the substituents listed below), or S(O)_(n) (where n isan integer from 0 to 2), the remaining ring atoms being C, where one ortwo C atoms may optionally be replaced by a carbonyl group. Theheterocyclyl ring may be optionally substituted independently with one,two, or three substituents selected from alkyl, cycloalkyl,cycloalkyl-alkyl, arylalkyl, halo, nitro, cyano, cyanoalkyl, hydroxy,alkoxy, amino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,—(CR′R″)_(n)—COR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, R is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl, phenyl, or phenylalkyl), —(CR′R″)_(n)—COOR (n is aninteger from 0 to 5, R′ and R″ are independently hydrogen or alkyl, andR is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, phenyl orphenylalkyl), —(CR′R″)_(n)—C(=Q)NR^(a)R^(b) (where Q is O or S, n is aninteger from 0 to 5, R′ and R″ are independently hydrogen or alkyl, andR^(a) and R^(b) are, independently of each other, hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heteroalkyl, phenyl or phenylalkyl), or—(CR′R″)_(n1)—S(O)_(n)R^(d) (where n1 is an integer from 0 to 5, R^(d)is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl,aryl, aralkyl, amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl,and n is an integer from 0 to 2). More specifically the termheterocyclyl includes, but is not limited to, tetrahydropyranyl,piperidino, N-methylpiperidin-3-yl, piperazino,4-methanesulfonyl-1-piperazino, 4-dimethylaminosulfonyl-1-piperazino,N-methylpyrrolidin-3-yl, 3-pyrrolidino, 2-pyrrolidon-1-yl, morpholino,thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,pyrrolidinyl, and the derivatives thereof.

[0044] “Heterocyclylalkyl” means a radical —R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heterocyclyl group as defined herein,e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl,3-piperidinylmethyl, and the like.

[0045] “Heterosubstituted cycloalkyl” means a cycloalkyl group whereinone, two, or three hydrogen atoms are replaced by substituentsindependently selected from the group consisting of cyano, cyanomethyl,hydroxy, hydroxymethyl, alkoxy, amino, acylamino, mono-alkylamino,di-alkylamino, —SO_(n)R (where n is an integer from 0 to 2 and when n is0, R is hydrogen or alkyl and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, amino, acylamino,mono-alkylamino, di-alkylamino, or hydroxyalkyl), or —NHSO₂R where R isalkyl or aryl. Examples include 4-hydroxycyclohexyl, 2-aminocyclohexyletc.

[0046] “Hydroxyalkyl” means an alkyl radical as defined herein,substituted with one or more, preferably one, two or three hydroxygroups, provided that the same carbon atom does not carry more than onehydroxy group. Representative examples include, but are not limited to,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxymethyl-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-hydroxymethyl-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-hydroxymethyl-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-hydroxymethyl-2-hydroxyethyl. Accordingly, asused herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

[0047] “Optionally substituted phenyl” means a phenyl ring which isoptionally substituted independently with one to four substituents,preferably one or two substituents selected from alkyl, cycloalkyl,cycloalkyl-alkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino,mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR(where R is hydrogen, alkyl, phenyl or phenylalkyl, —NHS(O)₂R^(f) (whereR^(f) is alkyl or aryl), —NHCOR^(c) (where R^(c) is amino, alkylamino,dialkylamino or (C₁-C₄)alkoxy), —(CR′R″)_(n)—COOR (where n is an integerfrom 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R ishydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl),—(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R^(a) and R^(b) are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl, (C₁-C₄)alkoxy or phenylalkyl) or or any 2adjacent carbon atoms are substituted by —O(CH₂)_(n)O—(where n is 1 or2).

[0048] “Leaving group” has the meaning conventionally associated with itin synthetic organic chemistry i.e., an atom or group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo,iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N, O-dimethylhydroxylamino, and the like.

[0049] “Pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

[0050] “Pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

[0051] (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or

[0052] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

[0053] “Pro-drugs” means any compound which releases an active parentdrug according to Formula (I) in vivo when such prodrug is administeredto a mammalian subject. Prodrugs of a compound of Formula (I) areprepared by modifying functional groups present in the compound ofFormula (I) in such a way that the modifications may be cleaved in vivoto release the parent compound. Prodrugs include compounds of Formula(I) wherein a hydroxy, amino, or sulfhydryl group in a compound ofFormula (I) is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, or sulfhydryl group, respectively.Examples of prodrugs include, but are not limited to esters (e.g.,acetate, formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds ofFormula (I), and the like.

[0054] “Protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in T. W.Greene and P. G. Futs, Protective Groups in Organic Chemistry, (Wiley,2nd ed. 1999) and Harrison and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (John Wiley and Sons. 1971-1996).Representative amino protecting groups include formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES),trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC)and the like. Representative hydroxy protecting groups include thosewhere the hydroxy group is either acylated or alkylated such as benzyland trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers,trialkylsilyl ethers and allyl ethers.

[0055] “Treating” or “treatment” of a disease includes:

[0056] (1) preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease,

[0057] (2) inhibiting the disease, i.e., arresting or reducing thedevelopment of the disease or its clinical symptoms, or

[0058] (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

[0059] “A therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

[0060] “Optional” or “optionally” in the above definitions means thatthe subsequently described event or circumstance may but need not occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“heterocyclo group optionally mono- or di- substituted with an alkylgroup” means that the alkyl may but need not be present, and thedescription includes situations where the heterocyclo group is mono- ordisubstituted with an alkyl group and situations where the heterocyclogroup is not substituted with the alkyl group.

[0061] Compounds that have the same molecular formula but differ in thenature or sequence of bonding of their atoms or the arrangement of theiratoms in space are termed “isomers”. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

[0062] The compounds of this invention may exist in stereoisomeric formif they possess one or more asymmetric centers or a double bond withasymmetric substitution and, therefore, can be produced as individualstereoisomers or as mixtures. Unless otherwise indicated, thedescription is intended to include individual stereoisomers as well asmixtures. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art (see discussion inChapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, JohnWiley and Sons, New York, 1992).

[0063] The compounds of the present invention can also be produced inradiolabeled form and are useful in assays for evaluating the bindingcapabilities of compounds that interact with IKKα and with IKKβ.

[0064] Embodiments of the Invention

[0065] Compounds

[0066] In one aspect, the present invention provides compounds useful inthe treatment of inflammatory, metabolic or malignant conditions, havingthe formula:

[0067] In Formula (I), one of either V or X is N and the other is—CR^(a), or both V and X are —CR^(a) (where each R^(a) is independentlyhydrogen, alkyl, cycloalkyl or cycloalkylalkyl). Preferably, V is N andX is CH.

[0068] Y represents O, S or N(R), wherein R is H, CN, NO₂,(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl,(C₃-C₁₀)alkenyl or (C₂-C₁₀)alkynyl. Preferably, Y is O or S. Morepreferably Y is S.

[0069] Z represents H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl orN(R²)(R³) where R² and R³ are each independently H, (C₁-C₁₀)alkyl,(C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, or (C₁-C₁₀)heteroalkyl, or R² and R³ can becombined to form a 5-7-membered heterocyclyl ring.

[0070] Preferably, Z is (C₁-C₆)alkyl or N(R²)(R³). More preferably Z isNHMe or NH₂, most preferably Z is NH₂.

[0071] R¹ represents H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl,heterocyclyl, heterocyclylalkyl, aryl, aryl(C₁-C₄)alkyl,aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl,heteroaryl(C₁-C₄)heteroalkyl, or alkylene-C(O)R¹¹.

[0072] R¹¹ is hydrogen, (C₁-C₆)alkyl or NR¹²R¹³ (where R¹² and R¹³ areindependently hydrogen, (C₁-C₆)alkyl or heteroalkyl);

[0073] Preferably, R¹ is (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl,heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl or alkylene-C(O)R¹¹. Morepreferably, R¹ is (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl orheterocyclylalkyl.

[0074] R⁴ represents H, alkyl, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl. Preferably R⁴is H or alkyl. Most preferably, R⁴ is H.

[0075] A represents H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl,heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl,aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl,heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl or R^(a)NHC(═X)—wherein R^(a) is. (C₁-C₄)alkyl or aryl and X is O or S.

[0076] Preferably, A is (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl,(C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstitutedcycloalkyl, aryl, aryl(C₁-C₄)alkyl, or heteroaryl. More preferably, Arepresents (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl,heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl or heteroaryl.

[0077] B represents a substituted or unsubstituted five- or six-memberedaromatic ring containing at least one nitrogen atom, and from 0 to 3additional heteroatoms, wherein the B ring substituents are selectedfrom halogen, CF₃, CF₃O, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino, andcarboxamido . Preferably, the substituents on B are halo, CF₃, CH₃ oramino, more preferably CH₃.

[0078] Preferably, B contains a nitrogen atom at a position two atomsaway from the atom attaching B to the remainder of the molecule. Morepreferably, B is selected from substituted or unsubstituted imidazolyl,substituted or unsubstituted thiazolyl and substituted or unsubstitutedtriazolyl. Still more preferably, B is selected from1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl,5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl,imidazol-1-yl and 4-methyl-1,2,4-triazol-3-yl.

[0079] The letter U represents NR⁵, O or S, wherein R⁵ is H or(C₁-C₆)alkyl. Preferably, U represents NR⁵. More preferably, R⁵ is H,i.e. U is NH.

[0080] In another group of embodiments, V is CH and X is N. Within thisgroup of embodiments, Y is preferably O or S, more preferably S.Preferably, Z is (C₁-C₆)alkyl or N(R²)(R³). More preferably Z is NHMe orNH₂, most preferably Z is NH₂.pPreferably, R⁴ is H or CH₃, morepreferably H. Preferably, A is either selected from (C₁-C₁₀)alkyl,(C₁-C₁₀)heteroalkyl, aryl(C₁-C₄)alkyl, (C₃-C₇)cycloalkyl and aryl. Also,preferred in this group of embodiments are those in which B contains anitrogen atom at a position two atoms away from the atom attaching B tothe remainder of the molecule. More preferably, B is selected fromsubstituted or unsubstituted imidazolyl, substituted or unsubstitutedthiazolyl and substituted or unsubstituted triazolyl. Also, preferred inthis group of embodiments are those in which U is NR⁵, more preferablyNH.

[0081] In another group of embodiments, V is CH and X is CH. In yetanother group of preferred embodiments, Y is S; Z is NH₂; and R¹ is CH₃.In this group of embodiments, preferred groups for each of A and B arethe same as have been described above.

[0082] A number of different substituent preferences have been givenabove and following any of these substituent preferences results in acompound of the invention that is more preferred than one in which theparticular substituent preference is not followed. However, thesesubstituent preferences are generally independent, although somepreferences are mutually exclusive, and following more than one of thesepreferences may result in a more preferred compound than one in whichfewer of the substituent preferences are followed.

[0083] Particularly preferred compounds of the present invention areselected from those provided in the Examples that follow.

[0084] The present invention further provides methods of preparinganti-inflammation agents, comprising contacting a precursor compoundhaving the formula:

[0085] wherein A, U, V, X, B and R⁴ are as defined in the Summary of theInvention. with a compound having the formula:

[0086] wherein Y is selected from the group consisting of O and S and Zand R1 are as defined in the Summary of the Invention under conditionssufficient to produce compounds having the formula:

[0087] wherein each of A, B, R¹, R⁴, U, V, X, Y and Z have the meaningsprovided above.

[0088] Exemplary conditions are provided in the examples below, with theunderstanding that the skilled practitioner can adjust solvents,temperature, time of reaction, workup conditions and the like to producethe desired compounds.

[0089] In view of the methods provided herein, one of skill will alsoappreciate that certain compounds are particularly useful in thepreparation of the subject antiinflammation agents. Accordingly, thepresent invention provides in another aspect compounds of the formula:

[0090] wherein V, X, A, U, B and R⁴ are as defined in the Summary of theInvention.

[0091] Compositions

[0092] In addition to the compounds provided above, the presentinvention further provides pharmaceutical compositions comprising one ormore of the subject compounds in admixture with a pharmaceuticallyacceptable excipient.

[0093] In one embodiment, the invention provides the subject compoundscombined with a pharmaceutically acceptable excipient such as sterilesaline or other medium, water, gelatin, an oil, etc. to formpharmaceutically acceptable compositions. The compositions and/orcompounds may be administered alone or in combination with anyconvenient carrier, diluent, etc. and such administration may beprovided in single or multiple dosages. Useful carriers include solid,semi-solid or liquid media including water and non-toxic organicsolvents.

[0094] In another embodiment, the invention provides the subjectcompounds in the form of a pro-drug, which can be metabolically orchemically converted to the subject compound by the recipient host. Awide variety of pro-drug derivatives are known in the art such as thosethat rely on hydrolytic cleavage or oxidative activation of the prodrug.

[0095] The compositions may be provided in any convenient form,including tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, suppositories, etc. As such, the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

[0096] Still other compositions of the present invention are those thatcombine two or more of the present compounds in one formulation, or onecompound from the present invention with a second anti-inflammatory,antiproliferative or antidiabetic agent.

[0097] Methods of Use

[0098] In yet another aspect, the present invention provides methods oftreating IKK-mediated conditions or diseases by administering to asubject having such a disease or condition, a therapeutically effectiveamount of a compound of Formula (I) above. The “subject” is definedherein to include animals such as mammals, including, but not limitedto, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice and the like.

[0099] The term “therapeutically effective amount” means the amount ofthe subject compound that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician.

[0100] Diseases and conditions associated with inflammation, infectionand cancer can be treated with the present compounds and compositions.In one group of embodiments, diseases or conditions, including chronicdiseases, of humans or other species can be treated with inhibitors ofIKK function. These diseases or conditions include: (1) inflammatory orallergic diseases such as systemic anaphylaxis or hypersensitivityresponses, drug allergies, insect sting allergies; inflammatory boweldiseases, such as Crohn's disease, ulcerative colitis, ileitis andenteritis; vaginitis; psoriasis and inflammatory dermatoses such asdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria; vasculitis; spondyloarthropathies; scleroderma; respiratoryallergic diseases such as asthma, allergic rhinitis, hypersensitivitylung diseases, and the like, (2) autoimmune diseases, such as arthritis(rheumatoid and psoriatic), osteoarthritis, multiple sclerosis, systemiclupus erythematosus, diabetes mellitus, glomerulonephritis, and thelike, (3) graft rejection (including allograft rejection andgraft-v-host disease), and (4) other diseases in which undesiredinflammatory responses are to be inhibited (e.g., atherosclerosis,myositis, neurological conditions such as stroke and closed-headinjuries, neurodegenerative diseases, Alzheimer's disease, encephalitis,meningitis, osteoporosis, gout, hepatitis, nephritis, sepsis,sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonarydisease, sinusitis and Behcet's syndrome); (5) in another group ofembodiments, diseases or conditions are treated with inhibitors of IKKfunction that will promote cell death; examples of these diseasesinclude, but are not limited to, neoplastic diseases such as solidtumors (e.g. non-Hodgins lymphoma), skin cancer, melanoma, lymphoma, anddiseases in which angiogenesis and neovascularization play a role; (6)other metabolic disorders that are sensitive to inhibition of TNF orIL-1 signaling, such as obesity for example.

[0101] Depending on the disease to be treated and the subject'scondition, the compounds of the present invention may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

[0102] In the treatment or prevention of conditions which require NF-κBm modulation an appropriate dosage level will generally be about 0.001to 100 mg per kg patient body weight per day which can be administeredin single or multiple doses. Preferably, the dosage level will be about0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg perday, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day.Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to5.0 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0,20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

[0103] It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

[0104] The compounds of the present invention can be combined with othercompounds having related utilities to prevent and treat inflammatory andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above.

[0105] For example, in the treatment or prevention of inflammation, thepresent compounds may be used in conjunction with an anti-inflammatoryor analgesic agent such as an opiate agonist, a lipoxygenase inhibitor,such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, suchas a cyclooxygenase-2 inhibitor, an interleukin receptor antagonist,such as an interleukin-1 receptor antagonist, an NMDA receptorantagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sulindac, tenidap, and the like.Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane,or dextramethorphan; a diuretic; and a sedating or non-sedatingantihistamine. Each of the above agents may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, in some cases a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention may bepreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) VLA-4 antagonists; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as methotrexate cyclosporin,tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d)antihistamines (H1-histamine antagonists) such as bromopheniramine,chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine,antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine,cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e)non-steroidal anti-asthmatics such as beta-adrenergic agonists(terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine,ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast,pranlukast, iralukast, pobilukast, SKB-106,203), leukotrienebiosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidalanti-inflammatory agents (NSAIDs) such as propionic acid derivatives(alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen,fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,tiaprofenic acid, and tioxaprofen), acetic acid derivatives(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamicacid, niflumic acid and tolfenamic acid), biphenylcarboxylic acidderivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam,sudoxicam and tenoxican), salicylates (acetyl salicylic acid,sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone,mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2(COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV(PDE-IV); (i) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), α-glucosidase inhibitors (acarbose) andglitazones (troglitazone, rosiglitazone and pioglitazone); (j)preparations of interferon beta (interferon beta-1.alpha, interferonbeta-1.beta.); (k) other compounds such as 5-aminosalicylic acid andprodrugs thereof, antimetabolites such as methotrexate, azathioprine and6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents; and (1)agents that directly or indirectly interfere with cytokine signalling,such as soluble TNF receptors, TNF antibodies, soluble IL-1 receptors,IL-1 antibodies, and the like. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

EXAMPLES

[0106] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMRspectra were recorded on a Bruker DPX 300 NMR spectrometer. Significantpeaks are tabulated in the order: number of protons, multiplicity (s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broadsinglet) and coupling constant(s) in Hertz. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Micromass PlatformLC electrospray mass spectrometer using the Shimadzu LC-8A HPLC forsample delivery. Normally the analyte was dissolved in DMSO and 20microliter was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 800 daltons. All compounds couldbe analyzed in the positive ESI mode, using acetonitrile/water with 0.1%trifluoroacetic acid as the delivery solvent.

[0107] General Scheme for Synthesis

[0108] The synthesis of the target compounds is generally accomplishedas shown in Scheme 1 by reaction of the appropriate aldehyde (or ketonewhen R⁴ is other than H) ii with the appropriately substituted hydrazinederivative. In some cases, the aldehyde (or ketone) intermediate ii isnot fully isolated or characterized, but is simply synthesized from thecorresponding acetal (or ketal) and used directly in the final reaction.The final products can be isolated and purified, if necessary, byfiltration, recrystallization and/or chromatography, as appropriate.

[0109] The starting acetals (or ketals) can be prepared by a variety ofmethods generally known to those skilled in the art of organicsynthesis. Representative methods for the synthesis of these compoundsare provided in the Examples below.

[0110] Preparation of Synthetic Intermediates

[0111] For compounds of the invention in which V═N, X═CH and R⁴ is H,one can synthesize the intermediate acetal using the following generalsynthetic Scheme 2:

[0112] Keto ester iii is reacted with thiourea to provide pyrimidinoliv. Compound iv is alkylated at the pendant thio group affordingpyrimidinol v. Conversion of the hydroxyl group of v to a chloridefollowed by a palladium cross coupling reaction using a tin derivativeyields vi. Oxidation of the sulfanyl group followed by nucleophilicdisplacement produces the target compound vii. (For sake ofexemplification, R¹⁰, R¹¹ and R¹³ are alkyl and R¹² is aralkyl.)

[0113] Alternatively, one can synthesize acetal vii following generalsynthetic Scheme 3:

[0114] Aldehyde viii is reacted with a propargyl anion (M is a metal)and subsequently oxidized to provide ketone ix. The combination ofketone ix with a thiopseudourea affords pyrimidine vi, which isconverted to vii as above.

Example 1

[0115] Synthesis of2-isopropylamino-6-(1-methyl-1-H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone.

[0116] Step 1

[0117] Ethyl diethoxyacetate (10.4 mL, 60.0 mmol) and EtOAc (9.0 mL, 90mmol) were heated at 85° C. and then treated with sodium metal (1.44 g,60 mmol) in small pieces. After 2 h of heating, an additional portion ofEtOAc was added (9.0 mL, 90 mmol) followed by an additional portion ofsodium metal (1.44 g, 60 mmol), and heating was maintained for anadditional 3 h. The reaction was then cooled to room temperature andstirred overnight. The reaction was then poured onto water, acidifiedwith 1 N HCl, and extracted with diethyl ether (3×). The organics werewashed with saturated NaHCO₃ (3×) and saturated NaCl, dried over MgSO₄,and concentrated in vacuo. The crude product was dried under vacuum (0.5mm Hg) while being heated in an oil bath at 80° C. to remove any ethylacetoacetate that may have been produced. To a solution of the crudeketo ester and thiourea (4.57 g, 60 mmol) in EtOH (45 mL), was added 25%NaOMe (13 mL, 57 mmol, Aldrich) and heated at reflux for 4 h. Thereaction was cooled for 10 minutes, diluted with water (50 mL), treatedwith benzyl bromide (9.4 g, 55 mmol), and then stirred warm. Crystalsformed after 5 minutes, and the reaction was allowed to cool to roomtemperature and sit undisturbed for 1 h. The white solid was dilutedwith water and filtered to give2-benzylsulfanyl-6-diethoxymethyl-pyrimidin-4-ol (9.5 g, 29.6 mmol,50%).

[0118] Step 2

[0119] The hydroxy pyrimidine (10.0 g, 31 mmol) was stirred with2-picoline (2.0 mL). To this was added phosphorus oxychloride (20 mL)while cooling the reaction to 0° C. The reaction was stirred for 2 h,allowing it to warm to room temperature, and then poured over ice. Theaqueous mixture was extraced with diethyl ether (3×), the ether extractswere combined and washed with water, saturated NaHCO₃, brine, and driedover MgSO₄. The ether was removed in vacuo, and the crude productimmediately placed in a mixture of 50 ml of absolute ethanol and 50 mltriethyl orthoformate, followed by the addition of p-toluenesulfonicacid (100 mg). The reaction was heated at reflux for 1.5 h, cooled toroom temperature, and diluted with diethyl ether. The mixture was washedwith water, saturated NaHCO₃, brine, and dried over MgSO₄. The solventwas removed in vacuo and the residue chromatographed over silica gel(EtOAc/hexanes 5:95) to give the chloride as an oil (7.9 g, 23 mmol,74%).

[0120] Step 3

[0121] A solution of the chloro pyrimidine (2.6 g, 7.7 mmol) and1-methyl-5-tributyltin-imidazole (3.0 g, 8.1 mmol), in benzene (20 mL)was deoxygenated by bubbling N₂ gas through for 2 minutes at which pointtetrakis(triphenylphosphine) palladium (0) was added (445 mg, 0.38 mmol)and the reaction was heated to reflux under N₂ for 3.5 h. The reactionwas cooled, placed on the top of a silica gel column and eluted withMeOH/CH₂Cl₂ 5:95 to give the pyrimidine imidazole as an oil (3.5 g),which contained some tributyl tin impurities.

[0122] Step 4

[0123] To a solution of the sulfide (3.5 g from the previous step) in amixture of 50 mL EtOHand 50 mL water was addedoxone (16 g). The reactionwas stirred for 12 h, diluted with saturated NaHCO₃, extracted withEtOAc (3×), washed with water and brine, and dried over MgSO₄. Afterremoval of solvents in vacuo, the residue was chromatographed on silicagel EtOAc/hexanes 1:1 followed by MeOH/CH₂Cl₂ 5:95) to give thecorresponding sulfone (1.01 g, 2.42 mmol, 31% for two steps).

[0124] Step 5

[0125] A solution of the sulfone (200 mg, 0.52 mmol) and isopropyl amine(1.0 mL) was stirred in THF (2.0 mL) at room temperature for 14 h. Themixture was placed on top of a silica gel column and purified(EtOAc/hexanes 1:1 followed by MeOH/CH₂Cl₂ 5:95) to give the desiredamino pyrimidine acetal (110 mg, 0.345 mmol, 66%).

[0126] Step 6

[0127] The acetal (410 mg, 1.28 mmol) was heated in a mixture of 1N HCl(3 mL) and THF (3 mL) for 1 h. The reaction was cooled and diluted withEtOAc and water. Solid Na₂CO₃ was added until the aqueous phase wasbasic, extracted with EtOAc (2×),the organic phase washed with brine anddried over MgSO₄. The solvents were removed in vacuo to give thealdehyde (200 mg, 0.816 mmol, 64%) as a solid,

[0128] Step 7

[0129] A solution of the aldehyde (50 mg, 0.204 mmol) and2-methyl-3-thiosemicarbazide (35 mg, 0.33 mmol, Aldrich) in EtOH (2 mL)was heated to 60° C. The reaction stirred for 14 h and then cooled toroom temperature. The precipitatewas removed by filtration, washed withwater (3×), and then with diethyl ether (3×) to give2-isopropylamino-6-(1-methyl-1-H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone (48 mg, 0.145 mmol, 71%). MS (ES+): 333.

[0130]2-n-butyl-6-(1-methyl-1-H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone was prepared as described in Example 1, but1-butylamine was substituted for isopropylamine in step 5. MS (EI): (M⁺)346.

[0131] Alternative synthesis of2-benzylsulfanyl-4-diethoxymethyl-6-(1-methyl-1H-imidazol-5-yl)-pyrimidine:

[0132] Step 1

[0133] To a solution of propiolaldehyde diethylacetal (2.0 g, 16 mmol,Aldrich) in 20 mL of dry THF at −78° C. was added n-butyllithium (6.4mL, 16 mmol) dropwise. The resulting yellow solution was allowed to warmto −20° C. over 45 min and then recooled in a dry-ice acetone bath. Tothis was added 2-t-butyldimethylsilyl-1-methylimidazole-5-carboxaldehyde(2.2 g, 10 mmol; prepared according to Walters, et. al. TetrahedronLett. 1994, 35, 8307-8310), in 10 mL of dry THF, the reaction mixturewas stirred for 15 min and then quenched with saturated ammoniumchloride. The reaction mixture was diluted with water and extracted withEtOAc. The EtOAclayer was washed with brine, dried over Na₂SO₄ and thesolvent concentrated. The crude product and MnO₂ (10 g) in 100 mL ofCH₂Cl₂ was stirred overnight. The reaction mixture was filtered throughCelite and washed well with CH₂Cl₂. The solvent was removed on a rotaryevaporator and the residue was purified by flash chromatography (silicagel, acetone/hexane15:85) to obtain the desired ketone as an oil (2.5 g,71%). ¹H NMR (CDCl₃): δ8.12 (s, 1H), 5.45 (s, 1H), 4.05 (s, 3H),3.9-3.61 (m, 6H), 1.25 (s, 3H), 0.96 (s, 9H), 0.43 (s, 6H). MS (EI):(M⁺+1) 351.

[0134] Step 2

[0135] A mixture of 2-benzyl-2-thiopseudourea hydrochloride (1.04 g, 5.1mmol, Aldrich), the above ketone (1.5 g, 4.28 mmol) and potassiumcarbonate (0.7 g, 5 mmol) was suspended in 20 mL of acetonitrile andheated at 80° C. overnight. The resulting mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, concentrated, and the residue was purified by flashchromatography (silica gel, MeOH/dichloromethane 3:97) to obtain of2-benzylsulfanyl-4-diethoxymethyl-6-(1-methyl-1H-imidazol-5-yl)-pyrimidineas an oil (1.3 g, 80%). ¹HNMR (CDCl₃) δ7.6 (s,1H), 7.4 (s, 1H), 7.35-7.3(m, 2H), 7.25-7.1 (m, 4H), 5-19 (s, 1H), 4.34 (s, 2H), 3.86 (s, 3H),3.7-3.5 (m, 4H), 3.15 (t, 6H). MS (EI): (M⁺+1) 385.

Example 2

[0136]2-(4-Methoxy-phenylamino)-6-(1-methyl-3H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone.

[0137] Step 1

[0138] To a solution of p-anisidine (600 mg, 4.87 mmol) in dry THF (5ml) was added N,N′-bis-Boc-1-guanylpyrazole (1.44 g, 4.63 mmol). Theresulting mixture was stirred at room temperature for 40 h. Afterremoving volatiles, the crude material was loaded onto a flash column(silica gel, 2% to 7.5% EtOAc/hexanes 2:98 followed by 7.5:92.5) to givethe corresponding protected guanidine (1.71 g) as a white solid. MS(ES+): 366.

[0139] Step 2

[0140] To a solution of the protected guanidine (1.7 g, 4.65 mmol) indry EtOAc (20 ml) was added tin(IV) chloride (2.2 ml, 4 eq). The mixturewas stirred for 1 h and then all volatiles were removed under vacuo.EtOAc (20 ml) was added and the material again stripped under vacuo(repeat one more time). MeOH (10 ml) was added and the material wasstirred for 1 minute and then placed under vacuo to remove 90% of thesolvent. Ether (15 ml) was added and the product slowly crystallizedout. The product was collected by filtration and washed with ether toafford 4-methoxyphenylguanidine hydrochloride (853 mg) as a pink-whitesolid. MS (ES+): 166.

[0141] Step 3

[0142] To a mixture of 4-methoxyphenylguanidine hydrochloride (850 mg,4.21 mmol) and 4,4-diethoxy-3-oxo-butyric acid ethyl ester (2.76 g,12.65 mmol) in dry ethanol (15 ml) was added K₂CO₃ (434 mg, 3.2 mmol).The mixture was heated to reflux overnight. Extra K₂CO₃ (1.16 g) wasadded and heating continued for 1 h. The material was cooled to roomtemperature and the EtOH was removed under vacuo. The remainder wastaken up in EtOAc (80 ml) and partitioned with an equal volume of water.The organic phase was collected and washed with an equal volume of 50%diluted brine. The aqueous phase was back-extracted with EtOAc (2×50ml), the organic phases combined, dried onver MgSO₄, filtered andconcentrated. The product was crystallized from hot EtOAc/hexanesproviding the corresponding pyrimidine (520 mg) as a fluffy whitepowder. MS (ES+): 320.

[0143] Step 4

[0144] The hydroxy pyrimidine was covered with phosphorus oxychloride (5ml) and stirred for 2 h. All volatiles were removed under vacuo. Toluene(20 ml) was added and then removed under vacuo (repeated once more). Theresidue was taken up in EtOAc (80 ml) and partitioned with an equalvolume of 5% aqueous NaHCO₃. The organic phase was collected and washedwith brine (80 ml). The aqueous phases were back-extracted with EtOAc(2×). The EtOAcphases were combined, dried over MgSO₄, filtered andstripped to provide the corresponding chloro pyrimidine (555 mg) as atan-orange semi-viscous oil. MS (ES+): 338.

[0145] Step 5

[0146] To a mixture of the chloro pyrimidine (545 g, 1.6 mmol) and1-methyl-(5-tributylstannyl)-imidazole (718 mg, 1.94 mmol) in drybenzene (20 mL) was added tetrakis(triphenylphosphine)-palladium(0) (60mg). The mixture was refluxed for 5.5 h under argon. Additional1-methyl-(5-tributylstannyl)-imidazole (350 mg) and palladium(0)catalyst (40 mg) were added and the mixture was heated for an additional8 h. After cooling to ambient temperature the solvent was removed andthe resultant material was purified by preparative TLC (MeOH/CH₂Cl₂1:9), which provided6-diethoxymethyl-4-(1′-methyl-imidazole-5′-yl)-2-(4-methoxyphenylamino)-pyrimidine(649 mg) as a light yellow powder. MS (ES+): 384.

[0147] Step 6

[0148] The acetal (635 mg, 1.3 mmol) was covered with 3 N aqueoushydrochloric acid (25 ml) and heated to 50° C. After stirring for 2 h,the material was cooled to room temperature and all of the volatileswere removed under vacuo. The remainder was taken up in a mixture ofEtOAc (80 mL) and 5% aqueous NaHCO₃ (80 ml) and stirred rapidly forabout 5 minutes. The material was transferred to a separatory funnel andthe organic phase was collected and washed with an equal volume ofbrine. The aqueous phases were back-extracted with EtOAc (2×80 mL),combined, dried over MgSO₄, filtered and concentrated to provide thecorresponding aldehyde (465 mg) as an orange powder. MS (ES+): 310.

[0149] Step 7

[0150] To a solution of the aldehyde (100 mg, 0.323 mmol) in dry EtOH(10 ml) was added 2-methyl-3-thiosemicarbazide (34 mg, 0.323 mmol). Themixture was heated at reflux for 7 h. The reaction was cooled to roomtemperature and the volume concentrated by 50% under vacuo. Thecrystallized product was collected by filtration. The crystals werewashed with ethanol (20 ml), followed by ethyl ether (20 ml), and driedunder vacuum for 48 h to provide2-(4-methoxy-phenylamino)-6-(1-methyl-3H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone. (93 mg); ¹H-NMR (300 MHz, DMSO-d₆) 9.35 (s,1H), 8.79 (s, 1H), 8.60 (s, 1H), 7.94 (d, 1H, J=1.0 Hz), 7.89 (s, 1H),7.89 (s, 1), 7.80 (s, 1H), 7.62 (d, 2H, J=9.0 Hz), 7.52 (s, 1H,), 6.90(d, 2H, J=9.0 Hz), 3.99 (s, 3H), 3.83 (s, 3H), 3.74 (s, 3H); MS (ES+):397.

[0151] Procedure described in Example 2, step 1 through step 7 werefollowed, but 3,4-methylenedioxyaniline was substituted for p-anisidineto provide2-(3,4-methylenedioxy-phenylamino)-6-(1-methyl-3H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone.; ¹H-NMR (300 MHz, DMSO-d₆) 9.41 (s, 1H),8.79 (s, 1H), 8.60 (s, 1H), 7.95 (d, 1H, J=1.0 Hz), 7.91 (s, 1H), 7.81(s, 1H,), 7.53 (s, 1H), 7.44 (s, 1H, br), 7.11-7.18 (m, 1H), 6.85 (d,1H, J=8.4 Hz), 5.98 (s, 2H), 4.01 (s, 3H), 3.83 (s, 3H); MS (EI): (M⁺)411.

Example 3

[0152] Synthesis of2-isopropylamino-6-thiazol-5-yl-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone

[0153] Step 1

[0154] A mixture of 2-benzylsulfanyl-4-chloro-6-diethoxymethylpyrimidine(850 mg, 2.5 mmol), 2-trimethylsilyl-5-tributylstannylthiazole (2.0 g),and PdCl₂(PPh₃)₂ (200 mg) in DMF (6 ml) was heated at 80° C. After 3 h,the mixture was partitioned between EtOAc and water. The crude productwas purified by prep TLC on silica gel ( EtOAc/hexanes 1:2) to obtainthe desired product (750 mg).

[0155] Step 2

[0156] The sulfide obtained above (750 mg) was dissolved in 40 ml ofMeOH and treated with excess oxone (4.0 g) in 20 ml of water. Thereaction mixture was stirred for 5 h at room temperature and then at 0°C. overnight. The mixture was partitioned between CH₂Cl₂ and water. Thecrude sulfone was dissolved in DMF (15 mL) and treated withisopropylamine (5 mL). After stirring overnight, the mixture waspartitioned between EtOAc and water, the organics separeted andconcentrated to dryness. The crude product was purified on prep TLC(EtOAc/hexane 1:1) to give the desired acetal pyrimidine (450 mg).

[0157] Step 3

[0158] The acetal (450 mg) was dissolved in 1:1 THF/3N HCl (30 ml ) andheated at 50° C. for 5 h. The reaction mixture was poured into aqueousNaHCO₃ and the product was extracted with CH₂Cl₂, dried over MgSO₄, andconcentrated to give an oil. The crude product was purified by prep TLC(EtOAc/hexane 1:1) to afford the desired aldehyde (260 mg).

[0159] Step 4

[0160] The aldehyde (130 mg) was suspended in EtOH (1 mL) and treatedwith 1.2 equivalents 2-methyl-3-thiosemicarbazide. After heatingovernight at 80° C., in a sealed tube, the2-isopropylamino-6-thiazol-5-yl-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone was filtered off and dried (61 mg) MS(ES+):336.

Example 4

[0161] Synthesis of6-imidazol-1-yl-2-isopropylamino-pyrimidine-4-carbaldehyde 2-methylthiosemicarbazone.

[0162] Step 1

[0163] A mixture of 2-benzylsulfanyl-4-chloro-6-diethoxymethylpyrimidine(850 mg, 2.5 mmol) and imidazole (2 eq) was heated at 80° C. in DMF (4ml) overnight. The mixture was partitioned between EtOAc and water. Theorganic layer separated, dried and concentrated to give the crudeproduct (910 mg) The crude product was carried on to the next step.

[0164] Step 2

[0165] The sulfide (910 mg) was dissolved in MeOH (40 mL) and treatedwith excess oxone (4.0 g) in water (20 mL). After stirring at roomtemperature for 5 h, the reaction mixture was partitioned between CH₂Cl₂and water. The crude sulfone was dissolved in DMF (15 mL) and treatedwith isopropylamine (5 mL). The reaction mixture was stirred overnightand then partitioned between EtOAc and water. The crude mixture waspurified by prep TLC (EtOAc) to give6-imidazol-1-yl-2-isopropylamino-pyrimidine-4-carbaldehyde diethylacetal(370 mg).

[0166] Step 3

[0167] The acetal (370 mg) was dissolved in 1:1 THF/3N HCl (30 mL) andheated at 50° C. for 5 h. The reaction mixture was poured into aqueousNaHCO₃ and the product was extracted with methylene chloride. The crudemixture was purified by prep TLC ( EtOAc) to give the correspondingaldehyde(170 mg).

[0168] Step 4

[0169] The aldehyde (170 mg) was suspended in EtOH (1.5 mL) and treatedwith 1.25 equivalents 2-methyl-3-thiosemicarbazide. After heatingovernight at 80° C., in a sealed tube, the desired product,6-imidazol-1-yl-2-isopropylamino-pyrimidine-4-carbaldehyde 2-methylthiosemicarbazone, was filtered off and dried(75 mg) MS(ES+):319.

Example 5 Synthesis of2-isopropylamino-6-(4-methyl-4H-[1,2,4]triazol-3-yl)-pyrimidine-4-carbaldehyde2-methyl thiosemicarbazone

[0170]

[0171] Step 1

[0172] 2-benzylsulfanyl-4-chloro-6-diethoxymethyl pyrimidine (5.0 g),0.05 eq. of Pd(OAc)₂, 0.055 eq. of 1,3-bis(diphenylphosphino) -propane(DPPP) and 1.5 eq. of K₂CO₃ were charged to the flask containingn-propanol (54 mL) and DMF (27 mL). The flask was purged with N₂following by CO (balloon). Reaction mixture was stirred at 90° C. underthe CO atmosphere overnight. A solution of citric acid was added to thereaction mixture, stirred for 15 min and the product was extracted withEtOAc. Organic phase was dried over MgSO₄ and the solvent was removed invacuum to afford the desired carboxylic acid (4.8 g, 93%). The materialwas used without purification.

[0173] Step 2

[0174] To a solution of the carboxylic acid (4.8 g) in 60 ml ofMeOH/CH₂Cl₂ (2:1) was added of TMS diazomethane (21 mL) by portions at0° C. The reaction mixture was stirred at 0° C. for 30 min after all ofthe reagent was added. Solvent was evaporated and the residue waspurified on a silica gel column (EtOAc/hexane 2:98 to 8:92) to yield thecorresponding ester (2.5 g, 50% ) as a colorless oil.

[0175] Step 3

[0176] To a solution of the ester sulfide (2.5 g, 7 mmol) in 50 ml ofMeOH was added a solution of oxone (13.0 g, 21 mmol) in water (100 mL).The reaction mixture was stirred at room temperature for 7 h. Thereaction mixture was partitioned between CH₂Cl₂ and water. Organics wereseparated, dried over MgSO₄, and the solvent was removed under vacuum.The product (1.9 g, 70%) was used in the next reaction withoutpurification.

[0177] Step 5

[0178] To a solution of the sulphone (1.9 g, 4.8 mmol) in THF (20 mL)was added isopropylamine (2.4 mL, 29 mmol). The reaction was stirred atroom temperature overnight.The solvent was removed in vacuum. Theresidue was purified by column chromatography on silica gel(EtOAc/hexane 5:95) to give the desired ester (1.2 g 86%) as a clearoil.

[0179] Step 6

[0180] A mixture of the methyl ester (1.2 g) and LiOH (1.5 g) in 120 mLof MeOH/H₂O/THF (1:1:4) was stirred at 60° C. overnight. KOH (0.5 g) and20 mL of THF were added and the reaction mixture was stirred at 60° C.for extra 48 h. The reaction mixture was poured on ice, acidified withacetic acid to pH 4.5-5 and extracted with CH₂Cl₂. The organic phase wasdried over MgSO₄, the solvent was removed and the residue was dried onhigh vacuum to remove all acetic acid. The crude product was purified onprep. TLC (EtOAc/hexane 3:7) to give the carboxylic acid (500 mg) as anoff-white solid.

[0181] Step 7

[0182] To a solution of the carboxylic acid (0.5 g, 1.8 mmol) in 30 mLof DMF were added 4-methyl-3-thiosemicarbazide (0.6 g, 5.4 mmol), HOBT(0.3 g, 2 mmol) and N-methylmorpholine (0.4 mL, 3.6 mmol). The mixturewas cooled in ice-water bath and EDC (1.0 g, 5.4 mmol) was added to thereaction. The reaction mixture was stirred for 18 h at room temperature.DMF was removed under high vacuum, EtOAc was added to the flask and thesolution was washed with 2.5N HCl (100 mL), brine (100 mL) and sat.NaHCO₃ (100 mL). The organic phase was dried over MgSO₄, and the solventremoved. The residue was purified on a prep TLC, (MeOH/CH₂Cl₂ 1:9) togive the desired product (0.51 g).

[0183] Step 8

[0184] Sodium metal (0.22 g) was dissolved in 10 mL of dry MeOH, theacyl semithiocarbazide (0.44 g, 1.2 mmol) was added and the reactionmixture was refluxed for 18 h under N₂. The reaction was cooled to roomtemperature, solvent was removed, the solids were dissolved in water andacidified with 10% HCl. The precipitate (0.12 g) was collected and thefiltrate was purified on prep TLC (MeOH/CH₂Cl₂ 1:9) to obtain 0.05g ofthe desired 3-mercapto-1,2,4-triazole derivative (0.17 g, 42%).

[0185] Step 9

[0186] The mercapto triazole (0.17 g) was dissolved in 5 mL of EtOH, andRaney-Nickel (0.4 g washed several times with EtOH) added to thesolution. The reaction mixture was refluxed for 18 h.The reaction wasfiltered through Celite, the solvent removed and the residue purified onprep TLC to give the corresponding acetal triazole (80 mg).

[0187] Step 10

[0188] To a solution of the acetal (80 mg) in 3 mL THF was added conc.HCl (3 mL) and refluxed for 18 h. The pH was adjusted to basic withaqueous NaHCO₃, and the aqueous phase extracted with CH₂Cl₂. Organicphase was dried over MgSO₄ and stripped. The residue was purified onprep. TLC (MeOH/CH₂Cl₂, 7:93) to give the corresponding aldehyde (40 mg,66%).

[0189] Step 11

[0190] The aldehyde (40 mg) and 2-methyl-3-thiosemicarbazide (17 mg ) in1 mL of EtOH was stirred at reflux for 24 h. The precipitate wasfiltered off and dried under vacuum to give2-isopropylamino-6-(4-methyl-4H-[1,2,4]triazol-3-yl)-pyrimidine-4-carbaldehyde2-methyl thiosemicarbazone (36 mg, 67%). MS (ES+): 334

Example 6

[0191] Synthesis of2-isopropylamino-6-(1-methyl-1H-imidazol-5-yl)-pyridine-4-carbaldehyde2-methyl thiosemicarbazone

[0192] Step 1

[0193] To a solution of 2,6-dichloropyridine-4-carboxylic acid (8.28 g,43.1 mmol, Aldrich) in dry THF (30 ml) was addedN,N′-diisopropyl-O-t-butylisourea (17 ml, 3.6 M) dropwise over 1 minute.The resulting mixture was stirred at room temperature overnight. Thematerial was then heated to 65° C. and additionalN,N′-diisopropyl-O-t-butylisourea (10 ml) was added dropwise. Themixture was stirred for 1 hour and cooled to room temperature. Afterremoving volatiles, the remainder was purified by flash silica gelcolumn (EtOAc/hexanes 5:95 followed by 7.5:92.5)affordingtert-butyl-2,6-dichloro-4-pyridine carboxylate (7.83 g, 73%) as a whitesolid. MS (ES+): 248.

[0194] Step 2

[0195] A mixture of tert-butyl 2,6-dichloro-4-pyridine carboxylate (1 g,4.03 mmol) and isopropyl amine (3.4 ml, 40.3 mmol) in dry DMSO (5 mL)was heated, in a sealed tube, at 105° C. for 5 h. The mixture was cooledto room temperature and a solution of saturated ammonium chloride (30ml) was added. The mixture was partitioned with EtOAc (40 mL) and theorganic layer was collected and washed with an equal volume of brine.The aqueous phases were back extracted with EtOAc (2×30 ml), the organicphases combined, dried over MgSO₄ and filtered. The crude material wasloaded onto a flash silica gel column (EtOAc/hexanes 1:9) to providedthe corresponding chloro pyridine (820 mg) as a light yellowsemi-viscous oil. MS (ES+): 271.

[0196] Step 3

[0197] To a mixture of the chloro pyridine (810 mg, 3.0 mmol) and1-methyl-(5-tributylstannyl)-imidazole (1.3 g, 3.6 mmol) in dry benzene(20 mL) was added tetrakis(triphenylphosphine)-palladium(0) (150 mg).The mixture was refluxed for 18 h under argon. Additional1-methyl-(5-tributylstannyl)-imidazole (1.4 g) and palladium(0) catalyst(150 mg) were added and the mixture was heated for an additional 5 h.After cooling to room temperature, the EtOAc 1.5:98.5) to afford thedesired pyridine (1.21 g.) in approximately 50% purity. MS (ES+): 317.

[0198] Step 4

[0199] The pyridine ester (1.2 g, 50% pure, 1.9 mmol) was taken up indry dioxane (20 ml). Sodium methoxide (1.02 g, 19 mmol) was added andthe mixture was heated to 80° C. After 30 minutes additional sodiummethoxide (1.02 g) was added and heating resumed for an additional 1.5h. The mixture was cooled to room temperature, water (30 ml) was added,and the crude mixture was transferred to a separatory funnel. Theaqueous phase was partitioned with ether (40 ml). The separated aqueousphase was condensed on the rotoevaporator, and traces of water wereremoved by azeotroping with toluene (2×60 ml), which afforded thecorresponding crude sodiumpyridine carboxylate, which was notcharacterized but used directly in the next step.

[0200] Step 5

[0201] The crude sodium carboxylate (1.9 mmol) was taken up in drymethanol (30 ml) and concentrated sulfuric acid (3 ml) was added. Themixture was heated to reflux for 3 h and then cooled to roomtemperature. Approximately 90% of the methanol was removed (using therotoevaporator); the remainder was taken up in water (45 ml) andpartitioned with an equal volume of ether. Ether (45 mL) was added tothe isolated aqueous phase and the mixture was brought to pH 9 by theaddition of solid Na₂CO₃. EtOAc (20 ml) was added and the mixture wastransferred to a separatory funnel. The organic phase was isolated andwashed with an equal volume of water. The aqueous phases were backextracted with EtOAc (2×45 ml), the organic phases were combined, driedover MgSO₄, filtered, and concentrated to afford the correspondingmethyl ester (402 mg) as a yellow-brown solid. MS (ES+): 275.

[0202] Step 6

[0203] The methyl ester (194 mg, 0.71 mmol) was taken up in dry THF(6ml) and cooled to −78° C. (dry ice/acetone bath). Lithium aluminumhydride (1.1 ml, 0.95 M in THF) was added via syringe and the reactionmixture was allowed to warm to room temperature over 45 minutes. Thereaction was quenched with acetic acid (10 drops, 50% in water) followedby saturated aqueous ammonium chloride (2 ml). The mixture was stirredfor 20 minutes and then water (30 ml), saturated aqueous ammoniumchloride (5 ml), and EtOAc(30 ml) were added and the material wastransferred to a separatory funnel. The EtOAc phase was collected andwashed with an equal volume of brine. The aqueous phases were backextracted with EtOAc (2×30 ml), combined, dried over MgSO₄, andconcentrated the corresponding primary alcohol (167 mg) as a goldenbrown viscous oil. MS (ES+): 247.

[0204] Step 7

[0205] Dess-Martin periodinane (413 mg, 0.98 mmol) was taken up in dryCH₂Cl₂ (7 ml) and dry tert-butyl alcohol (0.1 ml, 1.35 mmol) was added.The mixture was stirred for 15 minutes and then added to a flaskcontaining the alcohol (160 mg, 0.65 mmol) dissolved in CH₂Cl₂ (6 ml).The material was stirred for 30 minutes and then quenched by addition ofaqueous 1 N sodium hydroxide (4.1 ml) followed by ethyl ether (20 ml).After stirring for 15 minutes, additional 1 N sodium hydroxide (4.3 ml)was added followed by ethyl ether (30 ml), water (50 ml), and EtOAc (10ml). The material was transferred to a separatory funnel and the organicphase was collected and washed with an equal volume of 0.25 N aqueoussodium hydroxide, followed by water and brine. The aqueous phases wereback extracted with a solution of 90% ethyl ether/EtOAc (2×60 ml) andthe organic phases combined, dried over MgSO₄, filtered, andconcentrated. The residue was purified by prep. TLC (MeOH/EtOAc 16:84)to afford the corresponding aldehyde (141 mg) as a yellow semi-solid. MS(ES+): 245.

[0206] Step 8

[0207] To a solution of the aldehyde (139 mg, 0.57 mmol) in dry ethanol(10 ml) was added 2-methyl-3-thiosemicarbazide (60 mg, 0.57 mmol) andthe mixture was heated at reflux overnight. The reaction was cooled toroom temperature and the volume was reduced by 50% on therotoevaporator. Some crystals formed and were collected by filtration.The crystals were washed with ethanol (20 mL) followed by ethyl ether(20 mL) and then dried under vacuum for 48 h to provide2-isopropylamino-6-(1-methyl-1H-imidazol-5-yl)-pyridine-4-carbaldehyde2-methyl thiosemicarbazone (64 mg); ¹H-NMR (300 MHz, DMSO-d₆) 8.57 (s,1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.40 (s,1H), 6.63 (s, 1H), 6.51 (d, 1H, J=7.71 Hz), 3.98-4.15 (m, 1H), 3.96 (s,3H), 3.78 (s, 3H), 1.18 (d, 6H, J=6.4 Hz); MS (ES+): 332.

[0208] Procedure described in Example 6, step 2 through step 8 werefollowed, but benzylamine was substituted for isopropylamine to provide2-benzylamino-6-(1-methyl-1H-imidazol-5-yl)-pyridine-4-carbaldehyde2-methyl thiosemicarbazone; ¹H-NMR (300 MHz, DMSO-d₆) 8.58 (s, 1H), 8.34(s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 7.46 (d, 1H, J−1 Hz),7.18-7.36 (m, 6H), 6.76 (d, 1H, J=1 Hz), 4.56 (d, 1H, J=5.9 Hz), 3.78(s, 3H), 3.73 (s, 3H): MS (EI): M⁺380.

Example 7 Preparation of 2-(tetrahydropyran-4-ylmethyl)-4-tritylthiosemicarbazide

[0209]

[0210] Step 1

[0211] To a solution of 4-hydroxymethyl tetrahydropyran (Radziszewski,J. G. et al, J. Amer. Chem. Soc.; 1993, 115, 8401) (7.55 g, 65 mmol) inCH₂Cl₂ (80 ml) at 0° C. was added Et₃N (11.5 ml, 83 mmol) followed bymethanesulfonyl chloride (6.0 ml, 78 mmol). The reaction was stirred at0° C. for 2 hr and then at room temperature for 1 h. The reactiondiluted with CH₂Cl₂, washed with 10% NaHCO₃, water, brine, dried overNa₂SO₄ and concentrated to obtain the corresponding mesylate as a whitesolid (12.13 g).

[0212] Step 2

[0213] To a solution of the mesylate (12.13 g, 62.4 mmol) in ethanol (50mL) was added hydrazine monohydrate (30 mL) and the mixture was heatedto 60° C. for 2 h then concentrated to approx. 10 mL volume. Saturatedaq. sodium hydroxide (20 mL) and THF (50 mL) were added and the organicscollected, dried (NaSO₄), filtered and concentrated to afford and oilwhich was distilled (88-89° C., 2 mm/Hg) to give the desired hydrazineas a colorless liquid (5.7 g).

[0214] Step 3

[0215] To a stirred solution of the hydrazine (0.39 g, 3.0 mmol) in drydiethyl ether (20 mL) was added triphenylmethylisothiocyanate. Themixture was stirred at room temperature for 1 h and then the precipitatefiltered to afford 2-(tetrahydropyran-4-ylmethyl)-4-tritylthiosemicarbazide as a white solid (1.0 g). ¹H NMR (CDCl₃) δ9.47(s, 1H),7.17-7.36 (m, 15H), 3.92 -4.03 (m, 4H), 3.83 (s, 2H), 3.37 (td, J =11.5,2.5 Hz, 2H), 2.12 (m, 1H), 1.6-1.33 (m, 4H). MS (ES+): 432.

Example 8 Preparation of 2-(2-dimethyl ethyl)-4-trityl thiosemicarbazide

[0216]

[0217] Step 1

[0218] A solution of NaOH (8.0 g, 0.2 mol) in hydrazine hydrate (25 ml)was heated to 95° C. The oil bath was removed and2-dimethylaminoethylchloride hydrochloride (14.4 g, 0.1 mol) was addedportionwise to keep the temperature at 95-100° C. The reaction wasstirred at 95° C. for 1 h, the precipitate filtered and the residuedistilled (73.5-74.5° C., 15-20 mm Hg) to give the corresponding alkylhydrazine as a colorless liquid (3.8 g).

[0219] Step 2

[0220] To a solution of triphenylmethylisothiocyanate (3.0 g, 10 mmol)in ether (30 mL) was added the hydrazine (1.03 g, 10 mmol) at r.t. Thereaction was stirred for 2 h at room temperature, the precipitatefiltered to give 2-(2-dimethyl ethyl)-4-trityl thiosemicarbazide as awhite solid (2.58 g). ¹H NMR (CDCl₃) δ9.64 (s, 1H), 7.12-7.37 (m, 15H),4.71 (s, 1H), 4.15 (brt, J=5.1 Hz, 2H), 2.62 (brt, J=5.1 Hz, 2H), 2.26(s, 6H). MS (ES+): 405.

Example 9 Preparation of2-(2-hydroxy-2-methyl-but-4-yl)-4-trityl-thiosemicarbazide

[0221]

[0222] Step 1

[0223] To a solution of 3-methyl-1,3-butanediol (Fluka, 6.14 mL, 57.6mmol) in DCM (20 mL) at 0° C. under an atmosphere of nitrogen was addedtriethylamine (10 mL). p-Toluenesulfonyl chloride (11 g) in DCM (20 mL)was added dropwise over 4 h and the mixture was stirred for a further 3h at 0° C., then allowed to warm to room temperature overnight. Thereaction mixture was diluted with water (50 mL) and the organics wereseparated, washed with 1M HCl (50 mL), sat. aq. NaHCO₃ (50 mL) and water(20 mL). The organics were dried (Na₂SO₄), filtered and concentrated toafford the corresponding tosylate (13.4 g, 90%) as a white solid. ¹H NMR(CDCl₃) δ7.81 (d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 2H), 4.22 (t, J=7 Hz,2H), 2.47 (s, 3H), 1.88 (t, J=7 Hz, 2H), 1.23 (s, 6H).

[0224] Step 2

[0225] To a solution of the tosylate (6.55 g, 25 mmol) in ethanol (10mL) was added hydrazine monohydrate (15 mL) and the mixture was heatedto 60° C. for 2 h then concentrated to approx. 10 mL volume. Saturatedaq. sodium hydroxide (20 mL) and THF (50 mL) were added and the organicscollected, dried (NaSO₄), filtered and concentrated to afford thecorresponding hydrazine (1.8 g, 60%) as a colorless oil. ¹H NMR (CDCl₃)δ4.73 (s, 1H), 3.19 (s, 3H), 3.02-3.06 (m, 2H), 1.68 (t, J=6 Hz, 2H),1.26 (s, 6H). MS (ES+) 119.

[0226] Step 3

[0227] To a stirred solution of the hydrazine (0.8 g, 6.8 mmol) in drydiethyl ether (25 mL) was added triphenylmethylisothiocyanate (TransWorld Chemicals, 1.83 g, 6.0 mmol). The mixture was stirred for 1 h andthen hexanes (5 mL) was added and the mixture was filtered to afford2-(2-hydroxy-2-methyl-but-4-yl)-4-trityl-thiosemicarbazide as a whitesolid (0.62 g, 22%). ¹H NMR (CDCl₃) δ9.49(s, 1H), 7.21-7.36 (m, 15H),4.27 (t, J=6.3 Hz, 2H), 4.00 (s, 2H), 1.81 (t, J=6.6 Hz, 2H), 1.65 (s,1H), 1.24 (s, 6H). MS (ES+): 420.

Example 10 Preparation of2-(1-methanesulfonyl-piperidin-4-ylamino)-6-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-(2-hydroxy-2-methyl-but-4-yl)-thiosemicarbazone

[0228]

[0229] Step 1

[0230] A solution of the protected semithiocarbazide from Example 8 (70mg, 0.16 mmol) in TFA:DCM/1 :1 (2 ml) was stirred at room temperaturefor 1 h then concentrated in vacuo. Methanol (5 ml) was added and themixture re-concentrated. This step was repeated 3 times until a whitepowder was obtained. Ethanol (3 ml) and2-(1-methanesulfonyl-piperidin-4-ylamino)-6-(3-methyl-3-H-imidazol-4-yl)-pyrimidine-4-carbaldehyde(73 mg, 0.16 mmol) were added and the reaction mixture was stirred at60° C. overnight, cooled to room temperature and precipitate filtered toobtain2-(1-methanesulfonyl-piperidin-4-ylamino)-6-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-(2-hydroxy-2-methyl-but-4-yl)-thiosemicarbazone as a yellow solid(37.0 mg): mp 203.6-206.0° C.; ¹H NMR (DMSO-d₆-D₂O) δ8.66 (s, 1H), 8.18(s, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 4.52-4.62 (m, 2H), 4.14 (s, 3H),3.89-4.00 (m, 1H)3.52-3.61 (m, 2H), 2.88-2.97 (m, 2H), 2.86 (s, 3H),1.97-2.07 (m, 2H), 1.53-1.70 (m, 4H), 1.20 (s, 6H). MS (ES+): 524.

[0231] Compounds 11, 20, 21, 26, 28, 40, 74, 77, and 78 were prepared asdescribed above in Example 10 with the corresponding protectedthiosemicarbazide from Examples 7-9 and the corresponding aldehyde.

Example 11

[0232] Synthesis of6-(4-acetonitrile-phenylamino)-2-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone.

[0233] Step 1

[0234] To a solution of 2,6-dichloropyrimidine-4-carboxylate methylester (404 mg) in 10 mL of THF was added 4-aminophenyl acetonitrile andstirred at 60° C. under N₂ for 11 h. The solvent was removed in vacuumand the residue was purified on prep. TLC (hexanes/EtOAc, 9:1) to givethe desired 6-substituted regioisomer (150 mg) along with the otherisomer (100 mg).

[0235] Step 2

[0236] A solution of the 2-chloropyrimidine (0.53 g) and1-methyl-5-tributyltin-imidazole (1.0 g) in 20 mL of dry DMF was purgedwith Ar for a few minutes. (PPh₃)₂Pd(II)Cl₂ (63 mg) was added and thereaction mixture was stirred at 80° C. for 24 h. The reaction mixturewas poured into water and extracted with EtOAc (3×100 mL), the organicfraction was dried over MgSO₄ and the solvent was evaporated in vacuum.The crude product was purified on column (SiO₂, hexanes/EtOAc, 95:5) togive the desired 2-(imidazo-5-yl)-pyrimidine (0.22 g) as an oil.

[0237] Step3

[0238] To a solution of the methyl ester (0.1 g, 0.3 mmol) in 5 mL ofdry THF at −78° C. under N₂ was added a 1.0 M solution of LiAH₄ (0.32mL) in THF. After stirring at this temperature for 30 min, more of the1.0 M solution of LiAH₄ (0.15 ml) was added and 15 min later thereaction was quenched with saturated aqueous ammonium chloride. Thereaction mixture was partitioned between water and EtOAc. The organiclayer was dried over MgSO₄ and the solvent was removed in vacuum toyield a mixture of the corresponding alcohol and aldehyde (60 mg) whichwere separated on prep. TLC (CH₂Cl₂/MeOH, 95:5) to obtain the desiredaldehyde (30 mg) in pure form.

[0239] Step4

[0240] In a pressure tube were combined the aldehyde (30 mg) and2-methyl-3-thiosemicarbazide (15 mg) in 1.0 mL of EtOH, capped andstirred at 80° C. for 24 h under Ar. The precipitate was filtered off,and dried in vacuum to give6-(4-acetonitrile-phenylamino)-2-(1-methyl-1H-imidazol-5-yl)-pyrimidine-4-carbaldehyde2-methyl-thiosemicarbazone (15 mg) as yellow crystals. MS (ES+): 406.

Example 12

[0241] The following compounds were all prepared by similar methods tothose described in Examples 1-9.

MS data Cpd A V R¹ R⁴ Y Z (ES+) No CH₃(CH₂)₃— N CH₃ H S NH₂ 347 1 CH₃— NCH₃ H S NH₂ 305 2 (CH₃)₂CH— N CH₃ H S NH₂ 333 3 PhCH₂— N CH₃ H S NH₂ 3814

N CH₃ H S NH₂ 373 5

N CH₃ H S NH₂ 391 6

N CH₃ H S NH₂ 464 7

N CH₃ H S NH₂ NH₂(ES+) 375 8

N CH₃ H S NH₂ 359 9 PhCH₂CH₂— N CH₃ H S NH₂ 395 10 (CH₃)₂CH— N(CH₃)₂N(CH₂)₂— H S NH₂ 391 11 Ph— N CH₃ H S NH₂ 367 12 HO—(CH₂)₂— N CH₃H S NH₂ 335 13 PhCH₂— CH CH₃ H S NH₂ 380 14 (CH₃)₂CH— CH CH₃ H S NH₂ 33215 (CH₃)₂CHCH₂— N CH₃ H S NH₂ 347 16

N CH₃ H S NH₂ 345 17

N CH₃ H S NH₂ 375 18

N CH₃ H S NH₂ 382 19 PhCH₂— N (CH₃)₂N(CH₂)₂— H S NH₂ 438 20 PhCH₂— N

H S NH₂ 465 21 H— N CH₃ H S NH₂ 291 22

N CH₃ H S NH₂ 382 23

N CH₃ H S NH₂ 331 24 (CH₃)₂CH— N H H O NH₂ 303 25 (CH₃)₂CH— N

H S NH₂ 417 26 Ph— N H H O NH₂ 337 27 Ph— N

H S NH₂ 451 28

N CH₃ H S NH₂ 347 29

N CH₃ H S NH₂ 411 30

N CH₃ H S NH₂ 397 31

N CH₃ H S NH₂ 404 32

N CH₃ H S NH₂ 418 33

N CH₃ H S NH₂ 396 34

N CH₃ H S NH₂ 446 35

N CH₃ H S NH₂ 392 37

N CH₃ H S NH₂ 392 38

N CH₃ H S NH₂ 406 39

N

H S NH₂ 415 40

N CH₃ H S NH₂ 416 41

N CH₃ H S NH₂ 411 42

N CH₃ H S NH₂ 424 43

N CH₃ H S NH₂ 397 44

N CH₃ H S NH₂ 430 45

N CH₃ H S NH₂ 452 46

N CH₃ H S NH₂ 456 47

N CH₃ H S NH₂ 406 48 HO—(CH₂)₅— N CH₃ H S NH₂ 377 49 HO—(CH₂)₄— N CH₃ HS NH₂ 363 50

N CH₃ H S NH₂ 466 51

N CH₃ H S NH₂ 397 52

N CH₃ H S NH₂ 403 53

N CH₃ H S NH₂ 396 54

N CH₃ H S NH₂ 440 56

N CH₃ H S NH₂ 416 57

N CH₃ H S NH₂ 425 58 (CH₃)₃C— N CH₃ H S NH₂ 347 59

N CH₃ H S NH₂ 60

N CH₃ H S NH₂ 389 61

N CH₃ H S NH₂ 345 64

N CH₃ H S NH₂ 473 65

N CH₃ H S NH₂ 445 66

N CH₃ H S NH₂ 429 67

N CH₃ H S NH₂ 429 68

N CH₃ H S NH₂ 413 69

N CH₃ H S NH₂ 413 70

N CH₃ H S NH₂ 445 71

N CH₃ H S NH₂ 426 72

N CH₃ H S NH₂ 402 73

N

H S NH₂ 537 74 CH₃—SO₂—NCH₂(CH₃)₂CCH₂— N CH₃ H S NH₂ 453 75

N CH₃ H S NH₂ 395 76

N

H S NH₂ 77

N

H S NH₂ 495 78

N CH₃ H S NH₂ 445 79 CH₃—O—(CH₂)₂— N CH₃ H S NH₂ 347 80 CH₃—O—(CH₂)₃— NCH₃ H S NH₂ 363 81 (CH₃)₂CH—N—(O)C— N CH₃ H S NH₂ 376 82

N CH₃ H S NH₂ 423 83

N CH₃ H S NH₂ 466 84

N CH₃ H S NH₂ 407 85

N CH₃ H S NH₂ 481 86

N CH₃ H S NH₂ 466 87 CH₃—S(O)₂—N(CH₂)₃— N CH₃ H S NH₂ 425 88CH₃—S(O)₂—N(CH₂)₄— N CH₃ H S NH₂ 440 89

N CH₃ H S NH₂ 479 90

N CH₃ H S NH₂ 444 91

N CH₃ H S NH₂ 417 92 CH₃—S(O)₂—N—(CH₂)₂— N CH₃ H S NH₂ 412 93 (CH₃)₂CH—N H CH₃ S NH₂ 333 94

N CH₃ H S NH₂ 430 95

N HO(CH₃)₂C(CH₂)₂— H S NH₂ 524 96

N CH₃ H S NH₂ 427 97 (CH₃)₂CH— N CH₃ CH₃ S NH₂ 347 98

N CH₃ H S NH₂ 433 99

N CH₃ H S NH₂ 447 100

N CH₃ H S NH₂ 461 101

N CH₃ H S NH₂ 453 102

N CH₃ H S NH₂ 103 CH₃—C(O)—N—(CH₂)₃— N CH₃ H S NH₂ 390 104

N CH₃ H S NH₂ 439 105

N CH₃ H S NH₂ 431 106

N CH₃ H S NH₂ 425 107

N CH₃ H S NH₂ 488 108

N CH₃ H S NH₂ 439 109

N CH₃ H S NH₂ 480 110

N CH₃ H S NH₂ 431 111

N CH₃ H S NH₂ 438 112

N CH₃ H S NH₂ 460 113

N CH₃ H S NH₂ 368 114

N CH₃ H S NH₂ 440 115

N CH₃ H S NH₂ 427 116

N CH₃ H S NH₂ 361 117

N CH₃ H S NH₂ 440 118

N CH₃ H S NH₂ 460 119

N H H S NHCH₃ 333 120

N H S N(CH₃)2 347 121

N H S NH-n-C₄H₉ 375 122

N CH₃ H S NH₂ 418 123

N

H S NH₂ 537 124

N n-C₄H₉ H S NH₂ 495 125

N CH₃ H S NH₂ 407 126

N CH₃ H S NH₂ 418 127

N CH₃ H S NH₂ 424 128

N CH₃ H S NH₂ 424 129

N CH₃ H S NH₂ 424 130

N CH₃ H S NH₂ 461 131

N CH₃ H S NH₂ 412 132

N CH₃ H S NH₂ 412 133

N CH₃ H S NH₂ 435 134

N CH₃ H S NH₂ 435 135

N CH₃ H S NH₂ 425 136

N CH₃ H S NH₂ 439 137

N CH₃ H S NH₂ 474 138

N CH₃ H S NH₂ 438 139

N CH₃ H S NH₂ 425 140

N CH₃ H S NH₂ 397 141

N CH₃ H S NH₂ 397 142

N CH₃ H S NH₂ 399 143

N CH₃ H S NH₂ 373 144

N CH₃ H S NH₂ 439 145

N CH₃ H S NH₂ 410 146

N CH₃ H S NH₂ 454 147

N CH₃ H S NH₂ 368 148

N CH₃ H S NH₂ 424 149

N CH₃ H S NH₂ 395 150

N CH₃ H S NH₂ 370 151

N CH₃ H S NH₂ 345 152

N CH₃ H S NH₂ 426 153

N CH₃ H S NH₂ 409 154

N CH₃ H S NH₂ 411 155

N CH₃ H S NH₂ 409 156

N CH₃ H S NH₂ 454 157

[0242] The following compounds have also been prepared:

Example 13

[0243] This example provides an assay that is useful in evaluating andselecting a compound that modulates IKK-β kinase.

[0244] Assay Protocol for Measuring IKKβ Enzyme Inhibition

[0245] 96 well polystyrene microtiter plates were coated withNeutravidin (10 μg/mL in PBS, overnight at 4° C). The coating solutionwas removed and in 80 μl/well a kinase reaction mixture was added (20 mMTris-HCl, pH 7.5, 10 mM MgCl₂, 2 mM EGTA, 1 mM NaF, 0.5 mM benzamidine,1 mM DTT, 0.1% NP-40, 10 μM ATP, 1 μM of biotinylated substrate peptideKKERLLDDRHDSGLDSMKDEEYEQGK-bio, sequence derived from IκB-alpha). In 10μl/well in DMSO test compounds were added covering a final concentrationrange from 1 nM to 30μM. Recombinant full-length IKKβ enzyme was addedin 10 μl buffer containing Tris-HCl pH 7.5 20 mM, EGTA 2 mM, benzamidine0.5 mM, DTT 1 mM, NP-40 0.1%, MgCl₂ 10 mM to initiate the kinasereaction. The reaction mixture was incubated at room temperature for 45min. During this incubation the substrate peptide gets phosphorylated byIKKβ and gets captured onto the well's surface by Neutravidin. The platewas washed 3×with 150 μl distilled water to terminate the reaction andremove components of the reaction mixture.

[0246] A conventional chemiluminescent ELISA detection technique wasinitiated by adding 100 μl/well primary antibody (custom-made monoclonalantibody generated to recognize the phosphorylated epitope in thesubstrate peptide; used at 1:10,000 dilution) premixed with horseradishperoxidase (HRP) conjugated anti-mouse secondary antibody (commerciallyavailable from several sources; used at 1:10,000 dilution) in PBScontaining 2% BSA. The solution was incubated at room temperature for 40min on a shaker, then washed 3×with 150 μl of water. 100 μl/well10×diluted SuperSignal HRP substrate (from Pierce) was added and after 5min incubation the chemiluminescent signal was captured by a LabsystemsLuminoSkan luminometer. The point of 50% inhibition of IKKβ enzymeactivity (IC50) was determined by curve fitting with the LSW dataanalysis software (MDL, San Leandro, Calif.).

[0247] The compounds provided in Examples 1-5 and 9-11 displayed IC₅₀values of less than or equal to about 60 μM in the above assay.

[0248] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A compound having the formula:

wherein one of either V or X is N and the other is —CR_(a), or both V and X are —CR_(a) (where each R_(a) is independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; Y is selected from the group consisting of O, S and NR; wherein R is selected from the group consisting of H, CN, NO₂, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₃-C₁₀)alkenyl and (C₂-C₁₀)alkynyl; Z is selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₆)cycloalkyl-alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and N(R²)(R³); R¹ is selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl, —C(O)R¹¹ and alkylene-C(O)R¹¹; R¹¹ is hydrogen, (C₁-C₆)alkyl or NR¹²R¹³ (where R¹² and R¹³ are independently hydrogen, (C₁-C₆)alkyl or heteroalkyl); R² and R³ are each members independently selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl and (C₁-C₁₀)heteroalkyl, or R² and R³ can be combined to form a 5-7-membered heterocyclyl ring; R⁴ is selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl; A is selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₁-C₁₀)haloalkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl, heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl and R^(a)NHC(═X)— wherein R^(a) is (C₁-C₄)alkyl or aryl and X is O or S; B is a substituted or unsubstituted five- or six-membered aromatic ring containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF₃, CF₃O, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino and carboxamido; U is NR⁵, O or S; and, R⁵ is H or (C₁-C₆)alkyl.
 2. The compound of claim 1, wherein V is N and X is CH.
 3. The compound of claim 2, wherein Y is selected from the group consisting of O and S.
 4. The compound of claim 3, wherein R⁴ is H.
 5. The compound of claim 4, wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.
 6. The compound of claim 5, wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
 7. The compound of claim 6, wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl and 4-methyl-1,2,4-triazol-3-yl.
 8. The compound of claim 6, wherein U is NH.
 9. The compound of claim 8, wherein Z is N(R²)(R³).
 10. The compound of claim 9, wherein Z is NH₂.
 11. The compound of claim 10, wherein Y is S.
 12. The compound of claim 11, wherein R¹ is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹.
 13. The compound of claim 12, wherein A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl.
 14. The compound of claim 4, wherein R¹ is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹.
 15. The compound of claim 14, wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.
 16. The compound of claim 15, wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
 17. The compound of claim 16, wherein B is selected from the group consisting of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl and 4-methyl-1,2,4-triazol-3-yl.
 18. The compound of claim 16, wherein U is NH.
 19. The compound of claim 18, wherein Z is N(R²)(R³).
 20. The compound of claim 4, wherein Z is NH₂.
 21. The compound of claim 20, wherein A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl.
 22. The compound of claim 21, wherein R¹ is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹.
 23. The compound of claim 22, wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.
 24. The compound of claim 23, wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
 25. The compound of claim 24, wherein B is selected from the group consisting. of 1-methylimidazol-5-yl, 1-(trifluoromethyl)imidazol-5-yl, 5-methylimidazol-1-yl, 5-(trifluoromethyl)imidazol-1-yl, thiazol-5-yl, imidazol-1-yl and 4-methyl-1,2,4-triazol-3-yl.
 26. The compound of claim 24, wherein U is NH.
 27. The compound of claim 1, wherein V is CH and X is N.
 28. The compound of claim 27, wherein Y is O or S; Z is NH₂; and U is NH.
 29. The compound of claim 28, wherein A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl.
 30. The compound of claim 29, wherein R¹ is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹.
 31. The compound of claim 30, wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.
 32. The compound of claim 31, wherein B is selected from the group consisting of substituted or unsubstituted imidazolyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
 33. A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1.:
 34. The composition of claim 33, wherein V is N and X is CH.
 35. The composition of claim 34, wherein Y is selected from the group consisting of O and S.
 36. The composition of claim 35, wherein R⁴ is H.
 37. The composition of claim 36, wherein B contains a nitrogen atom at a position two atoms away from the atom attaching B to the remainder of the molecule.
 38. The composition of claim 37, wherein B is selected from the group consisting of substituted or unsubstituted imidazoyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl.
 39. The composition of claim 38, wherein Z is NH₂.
 40. The composition of claim 39, wherein R¹ is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹.
 41. The composition of claim 40 wherein A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl.
 42. A method of treating an inflammatory, metabolic or malignant condition, said method comprising administering to a subject in need of such treatment, an effective amount of a compound of claim
 1. 43. The method of claim 42, wherein V is N and X is CH.
 44. The method of claim 43, wherein the compound is administered orally.
 45. The method of claim 43, wherein the compound is administered topically.
 46. The method of claim 43, wherein the compound is administered intravenously or intramuscularly.
 47. The method of claim 43, wherein the compound is administered in combination with a second therapeutic agent, and wherein the second therapeutic agent is selected from the group consisting of prednisone, dexamethasone, beclosmethasone, methylprednisone, betamethasone, hydrocortisone, methotrexate, cyclosporin, rapamycin, tacrolimus, antihistamine drugs, TNF antibodies, IL-1 antibodies, soluble TNF receptors, soluble IL-1 receptors, TNF or IL-1 receptor antagonists, non-steroidal anti-inflammatory agents, COX-2 inhibitors, antidiabetic agents and anticancer agents.
 48. The method of claim 43, wherein the administering is sequential.
 49. The method of claim 43, wherein the inflammatory, metabolic or malignant condition is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, psoriasis, cancer, diabetes and septic shock.
 50. A method for the preparation of anti-inflammation agents comprising contacting a precursor compound having the formula:

wherein one of either V or X is N and the other is —CR_(a), or both V and X are —CR_(a) (where each R^(a) is independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; R⁴ is selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl; A is selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₁-C₁₀)haloalkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heterocyclyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl, heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl and R^(a)NHC(═X)— wherein R^(a) is (C₁-C₄)alkyl or aryl and X is O or S; B is a substituted or unsubstituted five- or six-membered aromatic ring containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF₃, CF₃O, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino and carboxamido; U is NR⁵, O or S; and, R⁵ is H or (C₁-C₆)alkyl with a compound having the formula:

wherein Y is selected from the group consisting of O, S and NR; wherein R is selected from the group consisting of H, CN, NO₂, (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₃-C₁₀)alkenyl and (C₂-C₁₀)alkynyl; Z is selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and N(R²)(R³); R¹ is selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heterocyclyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl, —C(O)R¹¹ or alkylene-C(O)R¹¹; and R² and R³ are each members independently selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₁-C₁₀)heteroalkyl, (C₃-C₇)cycloalkyl, or (C₃-C₇)cycloalkyl-alkyl, or R² and R³ can be combined to form a 5-7-membered heterocyclyl ring; under conditions sufficient to produce compounds having the formula:

wherein each of A, B, R¹, R⁴, U, V, X Y and Z have the meanings provided above.
 51. The method of claim 50, wherein: V is N and X is CH; Y is O or S; Z is NH₂; R¹ is is selected from the group consisting of (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, heterocyclylalkyl, heteroaryl(C₁-C₄)alkyl and alkylene-C(O)R¹¹; R⁴ is H; A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl; B is is selected from the group consisting of substituted or unsubstituted imidazoyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl; and U is NH.
 52. A compound having the formula:

wherein one of either V or X is N and the other is —CR_(a), or both V and X are —CR_(a) (where each R_(a) is independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl; R⁴ is selected from the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)haloalky (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl; A is selected from the group consisting of H, (C₁-C₁₀)alkyl, (C₃-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₁-C₁₀)heteroalkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-alkyl, (C₃-C₇) heterocyclylalkyl, heterocyclyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl, heteroaryl, heteroaryl(C₁-C₄)alkyl, heteroaryl(C₁-C₄)heteroalkyl, and R^(a)NHC(═X)— wherein R^(a) is (C₁-C₄)alkyl or aryl and X is O or S; B is a substituted or unsubstituted five- or six-membered aromatic ring containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF₃, CF₃O, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino, and carboxamido; U is NR⁵, O or S; and, R⁵ is H or (C₁-C₆)alkyl.
 53. The compound of claim 52, wherein: V is N and X is CH; R⁴ is H; A is selected from the group consisting of (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, (C₁-C₁₀)heteroalkyl, heterocyclyl, heterocyclylalkyl, heterosubstituted cycloalkyl, aryl, aryl(C₁-C₄)alkyl and heteroaryl; B is is selected from the group consisting of substituted or unsubstituted imidazoyl, substituted or unsubstituted thiazolyl and substituted or unsubstituted triazolyl; and U is NH. 